Factor VII Deficiency

Factor VII Deficiency

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Factor VII Deficiency is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • Alexander's disease
  • congenital factor VII deficiency
  • inherited factor VII deficiency

Disorder Subdivisions

  • None

General Discussion

Summary

Factor VII deficiency is a rare genetic bleeding disorder characterized by a deficiency or reduced activity of clotting factor VII. Clotting factors are specialized proteins that are essential for the blood to clot normally. Individuals with factor VII deficiency can experience prolonged, uncontrolled bleeding episodes. The severity of factor VII deficiency can vary greatly from one person to another. Some individuals may have no symptoms (asymptomatic); others may develop mild, moderate or potentially severe, life-threatening complications as early as in infancy. Factor VII deficiency is caused by mutations of the F7 gene and is inherited as an autosomal recessive disorder.



Introduction

Factor VII deficiency was first described in the medical literature by Dr. Alexander, et al. in 1951 and was referred to as prothrombin conversion accelerator deficiency. The disorder has also been known as Alexander's disease. In extremely rare instances, factor VII deficiency can be acquired during life; this report deals with the genetic form, which is present at birth (although symptoms may develop later).

Symptoms

The symptoms and severity of factor VII deficiency are highly variable; no consistent correlation between the amount of factor VII in the blood and overall severity is seen. Some individuals may not develop any symptoms (asymptomatic), including individuals with relatively low levels of factor VII. Other individuals may have mild cases that are only apparent after trauma or surgery. Mild symptoms can include chronic nosebleeds, easy bruising, and bleeding from the gums. Affected women may develop heavy and prolonged periods (menorrhagia).



More serious bleeding complications occur in some individuals and may mimic bleeding patterns seen in hemophilia. Bleeding into the joints (hemarthrosis) can result in progressive joint damage and degeneration, eventually limiting the range of motion of an affected joint. Soft tissue bleeding can result in bruising that seems spontaneous or out of proportion to an injury. Affected individuals can develop masses of congealed blood called hematomas that can cause symptoms due to compression of nearby structures or organs. Bleeding in the stomach, intestines and urogenital tract can also occur resulting in blood in the urine (hematuria) or black, tarry, bloody stools (melena or hematochezia).



Bleeding in severe factor VII deficiency can result in life-threatening complications. These include major gastrointestinal bleeds as well as head bleeds (intracranial hemorrhage), often during the first few weeks or months of life. Although quite rare, head bleeds have been reported in adults as well.



Individuals with factor VII deficiency may experience bleeding after surgery or minor procedures or following trauma or injury. Affected women may bleed excessively following childbirth (postpartum bleeding). Some newborns have experienced abnormal bleeding from the umbilical cord stump at birth.

Causes

Factor VII deficiency is caused by mutations of the F7 gene. These mutations are inherited in an autosomal recessive manner. Genetic diseases are determined by the combination of genes for a particular trait that are received from the father and the mother.



Recessive genetic disorders occur when an individual inherits the same abnormal gene from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass on the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.



The F7 gene creates (encodes) factor VII, which is a clotting factor. Clotting factors are specialized proteins that play an essential role in enabling the blood to clot. Clotting is the process by which blood clumps together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions to ultimately form a clot to plug a wound. This is referred to as the clotting (coagulation) cascade. The clotting cascade involves different substances in addition to clotting factors. Factor VII, which is produced (synthesized) in the liver, eventually interacts with other clotting factors and certain cells or substances, e.g. platelets or fibrinogen, to help to form a clot. Mutations of the F7 gene result in deficient levels of functional factor VII, which in affected individuals, prevents the blood from clotting properly. Consequently, affected individuals have difficulty stopping the flow of blood from a wound; but they do not bleed faster or more profusely than healthy individuals.



Individuals with factor VII deficiency often have varying levels of residual factor VII deficiency. In many disorders, the amount of residual protein activity correlates with the severity of the disease (e.g. little to no residual protein activity results in severe disease). However, in factor VII deficiency the severity of the disorder does not always correlate with the residual activity of factor VII, suggesting that additional genetic and environmental factors play a role in the severity of the disorder.

Affected Populations

Factor VII deficiency affects males and females in equal numbers. The disorder is estimated to affect 1 in 300,000 to 500,000 individuals in the general population. However, many cases of factor VII deficiency go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. The incidence of factor VII deficiency tends to be higher in countries where marriage to close relatives (consanguineous marriage) is more common. According to the medical literature, more than 200 cases of true factor VII deficiency have been reported. Because of the variable severity of factor VII deficiency, the age of presentation can vary widely from birth until adulthood.

Standard Therapies

Diagnosis

A diagnosis of factor VII deficiency is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized blood tests.



Clinical Testing and Work-Up

Specialized tests will include screening coagulation tests that measure how long it takes the blood to clot, specifically two tests known as activated partial thromboplastin time (aPTT) and prothrombin time (PT). Individuals with factor VII deficiency have a normal aPTT and a prolonged PT.



Further tests known as assays are required to confirm a diagnosis. An assay is a test that can measure the activity of certain substances in the blood. In affected individuals a factor VII assay will demonstrate reduced activity of factor VII.



Treatment

The specific therapeutic procedures and interventions for individuals with factor VII deficiency depend primarily on the severity of the individual's disease. Factors that will influence therapy decisions include specific symptoms present; the natural course of the disorder including underlying cause (congenital versus acquired); an individual's age and overall health (e.g., concomitant disease), risks of certain medications or procedures, personal preference; and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team, in careful consultation with the patient and/or parents, and based upon the specifics of the individual's case. Such a discussion will review the potential benefits and risks including possible side effects and long-term effects; consider patient preferences; and include other appropriate factors in order to come to a consensus.



Specific treatment options for acute bleeds in individuals with factor VII deficiency include recombinant factor VII, prothrombin complex concentrates, and fresh frozen plasma. Antifibrinolytics such as aminocaproic acid can help alleviate the bleeding symptoms.



NovoSeven® RT is a genetically engineered (recombinant) version of factor VII. Because it does not contain human blood or plasma, there is no risk of transmitting blood-borne viruses or other pathogens. NovoSeven has been well-tolerated and associated with few side effects. NovoSeven has been approved by the Food and Drug Administration (FDA) to treat bleeding episodes of individuals with congenital factor VII deficiency. NovoSeven® RT is manufactured by the pharmaceutical company Novo Nordisk. For more information, contact:



Novo Nordisk Inc.

100 College Road West

Princeton, NJ 08540



NovoSeven® RT Coagulation Factor VIIa (Recombinant)

1-877-668-6777

http://www.novosevenrt.com/



Individuals with factor VII deficiency have also been treated with prothrombin complex concentrates (PCCs), which are blood products that contain a concentrated form of four different clotting factors: II, VII, IX and X. However, the amount of each specific factor contained in these products can vary from one preparation to another, making it difficult to determine the most appropriate dosage. PCCs undergo a purification process to eliminate viruses and other pathogens. PCCs are associated with an increased risk of developing blood clots, especially following repeated administration.



Theoretically, factor VII deficiency can be treated with fresh frozen plasma. However, in clinical practice the very large volume required to stop bleeding renders this impractical, primarily due to the short half-life of factor VII. Half-life refers to the time it takes for half of the infused factor to breakdown and to disappear from the bloodstream.



Some individuals with factor VII deficiency may undergo preventative (prophylactic) therapy in an attempt to prevent or minimize future bleeding complications. Prophylactic therapy has been used for individuals with a history of bleeding into the joints or the brain. The decision to undergo prophylactic therapy in factor VII deficiency is made after careful consultation with a patient's medical team. The specific prophylactic regimen in factor VII deficiency is case dependent.



Additional treatment options for individuals with factor VII deficiency are symptomatic and supportive. For example, excessive menstrual bleeding in women may be treated by birth control pills or drugs known as antifibrinolytics. Genetic counseling may be of benefit for affected individuals and their families.



Individuals with factor VII deficiency will benefit from a referral to a federally-funded hemophilia treatment center. These specialized centers can provide comprehensive care for individuals with hemophilia and rare bleeding disorders, such as factor VII deficiency. The treatment center's medical team, headed by a hematologist with expert knowledge in bleeding disorders, will develop specific treatment plans and organize the monitoring and long term follow up of affected individuals, thus ensuring state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapist, social worker and genetic counselor) experienced in treating individuals with rare bleeding disorders.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.



For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:



Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

References

JOURNAL ARTICLES

Todd T, Perry DJ. A review of long-term prophylaxis in the rare inherited coagulation factor deficiencies. Haemophilia. 2010;16:569-583. http://www.ncbi.nlm.nih.gov/pubmed/19906159



Mandhyan R, Tiwari A, Cherian G. Congenital factor VII deficiency. Br J Anaesth. 2010;2:267-268.

http://bja.oxfordjournals.org/content/104/2/267.long



Boltin D, Boguslavski V, Goor Y, Elkayam. Primary factor VII deficiency. IMAJ. 2008;10:275-276. http://www.ima.org.il/imaj/ar08june-22.pdf



Mariani G, Lapecorella M, Dolce A. Steps toward an effective treatment strategy in congenital factor VII deficiency. Semin Hematol. 2006;43:S42-S47. http://www.ncbi.nlm.nih.gov/pubmed/16427385



Mariani G, Konkle BA, Ingersley J. Congenital factor VII deficiency: therapy with recombinant activated factor VII - a critical appraisal. Haemophilia. 2006;12:19-27. http://www.ncbi.nlm.nih.gov/pubmed/16409171



Acharya SS, Coughlin A, Dimichele M. Rare bleeding disorders registry: deficiencies of factors II, V, VII, X, XIII, fibrinogen and dysfibrinogenemias. J Thromb Haemost. 2004;2:248-256. http://www.ncbi.nlm.nih.gov/pubmed/14995986



Friederich PW, Henny CP, Messelink EJ, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomized trial. Lancet. 2003;361:201-205. http://www.ncbi.nlm.nih.gov/pubmed/12547542



INTERNET

Hartung H. Pediatric Factor VII Deficiency. Emedicine Journal, March 25, 2011. Available at: http://emedicine.medscape.com/article/960592-overview Accessed: February 5, 2012.



Ramanarayanan J, Krishnan GS. Factor VII. Emedicine Journal, May 19, 2011. Available at: http://emedicine.medscape.com/article/209585-overview Accessed: February 5, 2012.



Giansily-Blaizot M. Inherited Factor VII Deficiency. Orphanet encyclopedia, June 2004. Available at: http://www.orpha.net/data/patho/Pro/en/FactorVIIDeficiency-FRenPro916.pdf Accessed: February 5, 2012.

Resources

National Hemophilia Foundation

116 West 32nd Street, 11th Floor

New York, NY 10001

USA

Tel: (212)328-3700

Fax: (212)328-3777

Tel: (800)424-2634

Email: handi@hemophilia.org

Internet: http://www.hemophilia.org



Canadian Hemophilia Society

400-1255 University Street

Montreal

Quebec, H3B 3B6

Canada

Tel: 5148480503

Fax: 5148489661

Tel: 8006682686

Email: chs@hemophilia.ca

Internet: http://www.hemophilia.ca



NIH/National Heart, Lung and Blood Institute

P.O. Box 30105

Bethesda, MD 20892-0105

Tel: (301)592-8573

Fax: (301)251-1223

Email: nhlbiinfo@rover.nhlbi.nih.gov

Internet: http://www.nhlbi.nih.gov/



World Federation of Hemophilia

1425 René Lévesque Blvd. W. Suite 1010

Montreal

Quebec, H3G 1T7

Canada

Tel: 5148757944

Fax: 5148758916

Email: wfh@wfh.org

Internet: http://www.wfh.org/index.asp?lang=EN



Children's Cancer & Blood Foundation

333 East 38th Street, Suite 830

New York, NY 10016-2745

Tel: (212)297-4336

Fax: (212)297-4340

Email: info@childrenscbf.org

Internet: http://www.childrenscbf.org/



Hemophilia Federation of America

210 7th St. SE

Suite 200B

Washington, DC 20003

USA

Tel: (202)675-6984

Fax: (202)675-6983

Tel: (800)230-9797

Email: info@hemophiliafed.org

Internet: http://www.hemophiliafed.org



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



Irish Haemophilia Society

First Floor

Cathedral Court

New Street

Dublin, 7

Ireland

Tel: 353016579900

Fax: 353016579901

Email: info@haemophilia.ie

Internet: http://www.haemophilia.ie/



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

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